Gram-negative bacterial outer membrane and lipopolysaccharide matrix (OM/LPS)

The Gram-negative bacterial outer membrane (OM) is a specialized asymmetric lipid bilayer that serves as a critical permeability barrier against environmental stressors and antibiotics (Silhavy et al., 2010). Its outer leaflet is primarily composed of lipopolysaccharide (LPS), a complex glycolipid consisting of Lipid A, a core oligosaccharide, and an O-antigen (Raetz & Whitfield, 2002). This matrix provides structural integrity to the cell and acts as a potent endotoxin, capable of triggering severe immune responses and sepsis in host organisms (StatPearls, 2023). Therapeutic agents like polymyxins target the OM by binding to the negatively charged phosphate groups of LPS, displacing stabilizing divalent cations and causing membrane disruption (Poirel et al., 2017). Newer drug candidates focus on inhibiting the biosynthesis or transport of LPS (e.g., the Lpt pathway) or the assembly of outer membrane proteins (e.g., the Bam complex) to compromise the membrane's protective function (Sperandeo et al., 2017). These mechanisms are vital for overcoming the intrinsic resistance of pathogens like Pseudomonas aeruginosa and Acinetobacter baumannii (Iversen et al., 2019). Understanding the OM/LPS matrix is essential for developing treatments against multi-drug resistant Gram-negative pathogens.

Other names

Bacterial outer membraneLipopolysaccharideLPSEndotoxinOuter membrane matrixGram-negative cell envelope

Direct binding to the Lipid A component of lipopolysaccharide leads to the displacement of divalent cations (Mg2+ and Ca2+), resulting in the disruption of the outer membrane's structural integrity and increased permeability. Additionally, some agents inhibit the transport of LPS or the assembly of outer membrane proteins (e.g., BamA, LptD), leading to cell death or increased susceptibility to other antibiotics.